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Epigenetic regulation of neural stem cell differentiation.

机译：神经干细胞分化的表观遗传调控。

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摘要

In 1942, Conrad Waddington coined the term, "epigenetics". Historically, the word "epigenetics" was used to describe events that could not be explained by genetic mechanisms. Now, epigenetics is generally regarded as the molecular interface between genotype and phenotype---a collection of mechanisms that changes the gene expression or cellular phenotype without alterations in DNA sequence. For instance, almost all cell types in a multicellular organism contain identical genetic sequences; however, embryogenesis produces a vast diversity of cell types with stable gene expression and different morphology/functions. Thus, developmental processes, which are mediated by differentiation of pluripotent and tissue specific stem/progenitor cells, is profoundly influenced and potentially initiated by changes in epigenome, rather than the genome itself. Major epigenetic mechanisms include covalent modifications of histones and DNA. DNA cytosine methylation, the predominant chemical modification of the mammalian genome, is essential for mammalian development. However, our knowledge about their distribution and function in the genome remains limited. The main goal of my thesis research is to understand how de novo DNA methyltransferases, which is required for establishing new DNA methylation patterns, regulates gene expression and differentiation in neural stem/progenitor cells. By investigating the genome-wide occupancy of the de novo DNA methyltransferase 3a (Dnmt3a) and its role in gene regulation in multipotent neural stem/progenitor cells (NPCs), I found that Dnmt3a preferentially occupies and methylates genomic regions flanking proximal promoters of many moderately transcribed genes. Dnmt3a antagonizes binding of the polycomb repression complex 2 (PRC2) to these transcriptionally active/permissive Dnmt3a bound genes in a DNA methylation-dependent manner. Genetic ablation of Dnmt3a in NPCs causes a marked increase of PRC2-mediated repressive histone modification in genomic regions encompassing promoters and reduced transcription of a cohort of Dnmt3a bound genes, many of which are critical for proper differentiation of NPCs. We propose that the unexpected antagonism between de novo DNA methyltransferases and polycomb complexes may play a general role in epigenetic regulation of neural development.
机译：1942年，康拉德·沃丁顿（Conrad Waddington）创造了“表观遗传学”一词。历史上，“表观遗传学”一词用于描述无法通过遗传机制解释的事件。现在，表观遗传学通常被认为是基因型和表型之间的分子界面-一种在不改变DNA序列的情况下改变基因表达或细胞表型的机制的集合。例如，多细胞生物中几乎所有的细胞类型都包含相同的遗传序列。然而，胚胎发生产生具有稳定基因表达和不同形态/功能的多种细胞类型。因此，由多能性和组织特异性干/祖细胞分化介导的发育过程受到表观基因组而不是基因组本身的变化的深刻影响和潜在启动。主要的表观遗传机制包括组蛋白和DNA的共价修饰。 DNA胞嘧啶甲基化是哺乳动物基因组的主要化学修饰，对于哺乳动物的发育至关重要。但是，我们对它们在基因组中的分布和功能的了解仍然有限。本论文研究的主要目的是了解建立新的DNA甲基化模式所需的从头DNA甲基转移酶如何调节神经干/祖细胞中的基因表达和分化。通过研究从头DNA甲基转移酶3a（Dnmt3a）在全基因组中的占有率及其在多能神经干/祖细胞（NPC）中的基因调控中的作用，我发现Dnmt3a优先占据和甲基化了许多中等程度近端启动子侧翼的基因组区域转录的基因。 Dnmt3a以DNA甲基化依赖性方式拮抗多梳抑制复合物2（PRC2）与这些转录活性/允许的Dnmt3a结合基因的结合。在NPC中Dnmt3a的遗传消融会导致包含启动子的基因组区域中PRC2介导的抑制性组蛋白修饰显着增加，并减少Dnmt3a结合基因组的转录，其中许多基因对于NPC的正确分化至关重要。我们建议，从头DNA甲基转移酶和聚梳复合物之间的意外拮抗作用可能在神经发育的表观遗传调控中起一般作用。

著录项

  • 作者

    Wu, Hao.;

  • 作者单位

    University of California, Los Angeles.;

  • 授予单位 University of California, Los Angeles.;
  • 学科 Biology Neuroscience.;Health Sciences Pharmacology.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 215 p.
  • 总页数 215
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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